Treatment of certain allylic terpene alcohols and related compounds



United States Patent '0 TREATMENT- OF CERTAIN ALLYLIC ALCOHOIS AND RELATED COMPOUNDS Joseph P. Bain', Jacksonville, Fla., assignor to The Glidden Company, Cleveland, Ohio, a corporation of Ohio No Drawing. Application September 7, 1955 Serial No. 533,234

18 Claims. (Cl. 260-489) The present invention relates to the preparation of piperitols and isopiperitenols and esters of these, and the interconversion of cisand trans-isomers of members of this group of compounds.

It is known that piperitol exists in cisand trans-forms, as well as in optically active and racemic forms. The piperitols can be hydrogenated to menthols; see Simonsen, The Terpenes, volume I, and see MacBeth vand Shannon, Journal of The Chemical Society, 1952, page 2852. Isopiperitenol also occurs in optically active and in cisand trans-forms, as well as in racernic form. For preparation and properties of isopiperitenol see copending Serial No'. 348,825, filed April 14, 1953. Isopiperitenols can be selectively hydrogenated to piperitols or can be saturated by hydrogen to form menthols.

Also, the piperitols and isopiperitenols can be oxidized to the corresponding, ketones, piperitone or isopiperitenone, and these can be selectively hydrogenated to menthone or dehydrogenated to thym'ol.

Since menthol, thymol and menthone are valuable products used in the erfumery, flavoring and pharmaceutical industries, the production of suitable intermediates useful for their preparation is of special interest. Since l-menthol is the menthol isomer commanding the largest market, a process for producing it from domestic and cheap raw materials is of greatest interest.

Chromie acid d-plperltone H+ (aqueous medium) 1 ti fi .7

l-isomenthone I-trans-plpQrltoI l i l-isomenthol ill Pinenes or limonenes are suitable hydrocarbons to employ as raw materials for synthesis of the starting materials capable of conversion by our process to menthols, etc. by this instant invention. If the pinenes and limonene be optically active, the conversion products will likewise be optically active.

If racemic menthol, racemic menthone or if thymol is to be produced, the raw material need not be optically active, nor is it necessary to choose between cisand transforms of the piperitols or isopiperitenols. If-optically active menthol or menthone and derivatives are to be produced from piperitols by hydrogenation, followed by appropriate subsequent treatments, then it is necessary to start with optically active raw materials to produce piperitols and to choose that optically active cisor transform of piperitol which by hydrogenation and equilibration will yield the desired optically active menthol. If optically active piperitone is to be produced, it is necessary to employ optically active hydrocarbons, but it is not necessary to separate the piperitols or to interconvert them.

The relationships of the optically active hydrocarbons and intermediates to optically active menthol, etc. are shown in Chart 1 as these relationships affect our process. Chart 1 depicts the processing of some of the optically active products related to d-limonene and l-alpha-pinene.

With respect to Chart 1, it is desired to emphasize:

(l) The reversibility of the interconversions of the four-component-system, the cisand trans-forms of 2-menthene-1-ol and the cis-' and'trans-forrns of piperitol.

(2) The separability of cisand trans-piperitols by fractional distillation.

(3) The fact that l-menthol can result only by hydrogenation of d-cis-piperitol to d-neomenthol followed .b conversion to l-menthol. it i (4) The fact that l-trans-piperitol can yield only l-isomenthol which converts to d-menthol.

d-llmonene l-a-pinene l-trans-verbenol d-earvomenthene l x l-trans-verbenyl ether d-cls-amenthena-l-ol g i d-tmns-Z-menthene-l-ol Y l-trans-lsopiperitenyl methyl ether l-trans-piperitol d-els Piperitor perityl methyl ether (Fractionation) d-els-plperitol d-neomenthol -menthol That if l-menthol is desired, then the l-transpiperitol must be converted to d-cis-piperitol prior to the hydrogenation step.

It is evident that if the optical sign of any compound shown in Chart 1 is changed, then every other member of the optically active system of compounds must be changed.

Thus, if d-limonene is replaced by l-limonene, then l-piperitone can be prepared, and it may be hydrogenated to d-isomenthone, which can be converted to l-menthol. To produce l-menthol, d-trans-piperitol can be hydrogenated, and any l-cis-piperitol that is at hand can be converted to trans-piperitol prior to hydrogenation.

It is evident then that l-menthol can be produced from either l-limonene or from d-limonene, providing that proper choice of intermediates is made.

We have found that to produce mixtures of the piperitols that either "of the pure piperitols may be employed, and that there are several equivalents, as shown in Chart 2. These are (l) 2-menthene-1-ol, (2) 2-menthene-l-ol ethers and (3) piperityl ethers. Since the isopropyl group does not enter into the reactions, other starting materials containing a double bond at the l-position of the p-menthane skeleton are also suitable raw materials instead of the compounds specified by name. Such compounds include the A analogues, 8-alkoxypiperitols, 8-alkoxy-2-menthene-l-ols, 1,8-dialkoxy-2-menthemes, and the corresponding S-hydroxy and S-acetoxy compounds. Also esters of the above alcohols are capable of the same treatment.

It is accordingly an object of our invention to provide a process for treating an unsaturated tertiary alcohol or ether of the p-menthane series which is oxygenated at the 1-position and and where R is alkyl or cycloalkyl or hydrogen and where Y is isopropyl, 'isopropenyl, a-hydroxy-isopropyl, a-acyloxy-isopropyl or a-alkoxy-isopropyl.

Representative compounds of these types are:

(1) Cisand trans-Z-menthene-l-ol, see Simonsen, The Terpenes, volume I, 2nd edition, page 337, for preparation and properties of optically active cisand trans-forms, see copending Serial No. 377,000, filed August 27, 1953.

Distillation Ha cis-piperitol neomenthal 2 trans-piperitol isomenthol Fractional which possesses adouble bond at the 2-position to produce a secondary unsaturated alcohol oxygenated at the 3-position and possessing a double bond at the l position.

It is a further object to split ethers oxygenated at the 3-position and possessing a double bond at the l-position to the corresponding alcohols.

It is a further object to provide an economic process for preparation of piperitols. I

It is a further object to provide a process for interconversion of cisand trans-piperitol.

(2) 0cand ,B- (cis and trans) 2,8-p-menthadiene-1-ol, see copending Serial No. 377,000, filed August 27, 1953.

(3) Cisand trans-2-p-menthene-1,8-diol.

(4) Cisand trans-8-methoxy-2-menthene-l-ol, which 'can be made by air oxidation of 8-methoxy-carvomeuthene resulting from addition of methanol to limonene or to pinene, inaccordance with the procedures of Serial No. 377,000.

(5) l-alkoxy-2-menthenes and 1-alkoxy-2,8-p-menthadienes.

7 raw-aw MI??? :FPWW: mil-'3). P erityl and isopiperitenyl methylrethers. As'lshown-in Chart 2, the alcohol ester or ether of choice is treated with a carboxylic acid, whereby a mix ture of cisand trans-piperityl ester results. If the oxygenated starting material is one of the. types of ethers shown, then also the ester 1 isfo'rmed. I

Treatment of such starting materials with boiling water or cold aqueous acids produces a four-component equilibrium mixture consisting of Z-meuthene-l-ols andithe piperitols as shown in Chart 1. Under-such conditions,

however, the equilibrium mixture is poor in piperito'ls,

say 10 to 20%, and rich in the Z-menthene-l-ols. Since the latter are of no value for hydrogenation to menthol, it is desirable to convert .them to the piperitols to a greater extent than can be accomplished by 'a single stage simple aqueous a'cidequilibration. 1 I find that by employing suitable carboxylic acids, it is possible to convert any member or any mixture of members of the four-component equilibration system to a two-component system consisting almost exclusively of cisand trans-piperityl esters. The piperityl esters can be separated by fractionation if desired, but can alsotbe saponified to a mixture of the two piperitols andth'en fractionated as by distillation. Since the piperitols can be crystallized, their purification by crystallization isalso satisfactory. i

It is known that the piperitols readily dehydrate to form phellandrenes and alpha-terpinene. Acids readily provoke this undesirable decomposition, and in order to produce piperityl esters most economically, it is 'preferable to choose certain conditions of time and temperature depending upon the identity of thepiperitol precursor and the acid to be employed. Such choice of conditions is also desirable inproducing esters of isopiperitenol and related compounds. For example, when 2,8-p-menthadiene-1-ol is treated with excess formic acid at 25 C., isopiperitenyl formate is produced, but it decomposes to hydrocarbons so rapidly in the presence of this strong acid that the conversion at room temperature is not desirable for good yields of the isopiperitenyl formate. Much better yields of isopiperitenyl formate are obtained at temperatures of C. or below. On the other hand, weaker acids than formic, such as acetic acid can be employed satisfactorily at ordinary ambient temperatures of 20 to 35 C. and above, whereas still weaker acids, such as benzoic acid, are not effective at ambient or lower temperatures but can be employed at 50 to 100 C. I

It is possible, however, to modify the action of the acid to produce good yields of ester other than by relying on temperature modification alone. Thus, a strong acid such as formic acid can be bufiered as by addition of a quantity of a salt of a strong base and a weaker acid. Addition of such salts as sodium acetate, potassium phosphate, calcium propionate or alkali or alkali earth fortype solvents decrease the activity of carboxylic acids.

Other typesof solvents may tend to increase the activity of the acid. -For example, 'Kharasch and Reynolds found that phenols increased greatly the ability of benzoic acid to esterify alpha-pineneto produce borneol esters, see Journal of Organic Chemistry, volume 9, page 150 (1944). Other solvents such as benzene have little effect on our process. It is also known to. catalyze esterifica tions with a weak acidsbymeans of mineral acids, acid salts ,--boron fluoride and the-like. While I can employ these, I :prefcr to employ esterification conditions whereby such catalysts can be-avoided. i 1 .5.

Further, the temperature range most suitable for formation of these esters-depends on the concentration of the acid employed and upon the molar ratio of acid to the allylic terpeniccompound being esterified- In general, it is preferred to employ. anexcess of the carboxylic acid over that required to form the ester. If the compound to be treated is an alcohol such as 2-menthene-1-ol, theory requires that onemole of organic acid is required for one mole of alcohol and that one mole of water is produced. Ontheother hand, if the compound to be treated is a n etjher such as l-methoxy-Z-menthene, then theory requires two moles of acid for reaction to produce one mole of piperityl ester, one mole of methyl ester and mates to the formic acid prior to treatment of the organic alcohol or ether produces an esterifying reagent which can be used at higher temperatures than unbutfered formic acid without causing much formation of undesirable hydrocarbons.

' The dehydrating action of formic and other relatively strong acids can also be suppressed by addition of amines and other basic compounds to the formic acid without' It is known, for exam-l ple, that organic ethers, such as ethyl ether, dioxane,-

blocking its esterifying action.

is employed, and in somewhat excess, the two phases which are present when the .reaction is stopped will be found to separate easily; the upper phase is rich in esters and the lower phase is rich in aqueous formicacid. The

' aqueous formic acid phase canbe recycled several times until it becomes so weak in formic acid that it is no longer economic to employ it. During .the recycling operations, it may be found desirable to increaseathe temperature of each consecutive batch so that the last treatment takes place at say 25 C. of higher. The dilute aqueous unreacted formic acid or other acid can be recovered by'conventional methods, and likewise-the organic acid can be recovered from aqueous saponification liquors after saponifying the ester to recover the piperitolor other terpenic alcohol produced.

It is evident from the above thatit is not helpful to specify the temperature, the dissociation constants of suitable acids, the bufier orsolvent, if any, presence or absenceof catalysts, molar ratio of acid to ether oralcohol being treated, etc., since conditions of treatment are mutually dependent. The value of any particular treatment, however, is not difiicult to assay by infrared analysis or other examination of the product of treatment. Thus, since my invention is concerned with preparation of esters of piperitol, isopiperitenol and the like,-itis necessary only to determine the ester content of the acidfree reaction product by saponification or by instrue mental analysis. Infrared analysis supplies data not easily arrived at by other methods. Thus, saponification value provides only an estimate of the ester present and does not shed light on whether the treatment is insufdciently vigorous or too vigorous. Infrared analysis shows to What extent the starting material has been converted, the amount of desired product that is produced and to what extent the starting material has been converted to hydrocarbons or other undesirable products.

In conducting the treatment, I can employ pure compounds, but in general it will be found satisfactory to employ crude reaction products or fractiorisof these for treatment. Thus, one can employ the crude pyrolysis product obtained from l-transverbenyl ether and which consists of l-isopiperitenyl methyl ether as the major com-' ponent, but also. contains pseudo-verbenyl methylether and an enolmethyl ether. On treatmentwith flformic acid, the enol methyl ether is preferentially hydrolyzed and cyclized to yield a high boiling keto'n'e. "The isopiperitenyl methyl ether is hydrolyzed and esterified more slowly, and the pseudo-verbenyl methyl ether is unaffected. When the isopiperitenyl ester content reaches a maximum or prior thereto, the oil and aqueous layers are separated and the oil layer is saponified and fractionated to recover fractions rich in pseudo-verbenyl methyl ether, a mixture of the two isopiperitenols and the cyclic kctone. Hydrogenation of the mixed isopiperitenols yields a mixture of l-isomenthol and d-neomenthol. The two menthols are readily purified by fractionation, and each can then be equilibratcd by known means to obtain a mixture of four menthols. The l-isomenthol equilibrates to form d-menthol as the chief component of the equilibration mixture, whereas the d-neomenthol equilibrates to form a mixture rich in l-menthol. It is evident that only the cis-isopiperitenol is useful as a source of l-menthol in this particular case. Since cisand trans-isopiperitenols are more diflicult to separate by fractionation than are the piperitols, an alternative procedure would consist of selectively hydrogenating the mixture of isopiperitenols to a mixture of cisand transpiperitols and separating these. Hydrogenation of the cis-piperitol to neomenthol followed by equilibration could yield l-menthol. The separated trans-piperitol can be esterified with formic acid to produce a mixture of esters of cisand trans-piperitols suitable for saponification followed by fractional distillation to secure a further quantity of cis-piperitol for conversion to l-menthol.

Conversely, if the starting verbenyl ether is the dextroform, the operation is conducted to favor isolation of trans-isopiperitenol or trans-piperitol prior to hydrogenation, since l-menthol results from this choice of isomers at the piperitol or isopiperitenol stage.

The starting materials need not be optically pure, but are preferably so if optically pure products are to be produced. Optically pure menthols can be produced, however, from optically active, but optically impure, starting materials. Thus, if the optical purity of the starting material is about 50% and if proper choice is made of cis-trans forms of intermediates, then l-menthol of about 50% optical purity can be produced. The optically impure menthol can be separated, if desired, into its components, the optically pure menthol and racemic menthol. A suitable means for accomplishing this purpose would be esterification of the optically impure l-menthol with oxalic acid followed by crystallization of the ester, a known process.

Alternatively, if dl-menthol is the desired product, then optically inactive raw materials can be used, and no choice of isomers is required at the isopiperitenol or piperitol stages, since the mixture on hydrogenation, followed by equilibration, yields a mixture of menthols rich in dl-menthols and from which pure dl-menthol can be isolated by well-known methods.

It is also evident from study of Chart 1 that if d-pinene or l-lirnonene are available, the mixed piperitols resulting from processing need not be separated but can be oxidized with chromic acid, such as a Beclcmann mixture, to form l-piperitone, which on hydrogenation yields d-isomenthone, as is known. The d-isomenthone yields l-rnenthol when processed by known methods.

Choice of raw material for conversion to l-menthol will, of course, vary from time to time depending upon relative availability and cost, as well as upon cost of the various reagents and processing steps required for the particular type of conversion required. In any case, it is evident that I can employ either dextro- .or levo-forms of the raw material, providing I make the choice of the proper form of a suitable intermediate form, and that further if I wish to produce dl-menthol, such choice is not necessary.

The essence of the invention involves the production of a mixture of cisand trans-piperityl esters, or isopiperitenyl esters, or derivatives thereof, by treatment of any member or mixture of members of a class of com- 8 pounds including piperitols, piperityl ethers, the 2-menthene-l-ols and their ethers, or the corresponding group of compounds having unsaturation or substitution in the isopropyl group, in the presence of hydrogen ions with a material providing carboxylate ions.

As discussed above, either dilute aqueous acids or boiling water is capable of converting any member of the four-membered allylic family consisting of the two 2-menthene-l-ols plus the two piperitols into a mixture of all four members of the family. Such an equilibrated mixture, however, chiefly consists of the tertiary alcohols which do not yield menthol on hydrogenation. Therefore, simple aqueous acid equilibration suffers from the defect that the piperitols are present only to a limited extent, say 10 to 20%, if the equilibration is complete. In the present invention we are concerned with establishing equilibration conditions of such a nature that the product is very largely in the piperityl form and as an ester. If the 2-menthene-1-ols do esterify, it is only to a very slight extent, whereas the piperitols are readily esterified under our conditions. Also the ethers of the two Z-menthene-l-ols and the two piperitols are substantially equivalents to the free alcohols, except that more carboxylic acid is required to treat the ether and the ethers react somewhat more sluggishly. Once the piperityl esters are formed, they can be treated to saponify them to piperitols without formation of any of the tertiary alcohols.

As shown in the experimental section, the choice of carboxylic acid is not critical, since both strong and weak acids can be employed, either monocarboxylic or polycarboxylic. In general, however, we prefer to employ formic or acetic acids, since these acids are quite satisfactory and can be recovered economically either from diluted aqueous solution or from their sodium salts.

While dilute aqueous acid, say 30% formic acid, can be employed, it is to be understood that treatments with such aqueous acids does not cause complete esterification of the alcohols, and that while the esterified alcohols are in the piperityl form, the unesterified alcohols will be largely in the acid equilibrated form and therefore will be present largely as Z-menthene-l-ols. It is therefore desirable to cause as complete esterification as possible economically and to employ, say 70 to formic acid, if that acid is chosen. Where acetic acid is employed, still stronger acid strength is desirable, say 95 to and it will be found that addition of acetic anhydride may also be desirable after esterification has proceeded for a time.

In treating ethers, it will be found desirable to avoid anhydrous acids such as glacial acetic acid, since some water should be present to assist the ether cleavage. Glacial acetic acid, therefore, is preferably diluted to say 95% strength to secure faster ether splitting, and then stronger acid or anhydride added to complete the esterification of the alcohols formed on splitting.

Further, it has been found that the ratio of cisto transpiperitol esters is not identical or constant during the esterification. For example, when l-methoxy-Z-menthene is treated with formic acid and samples of oil are withdrawn and saponified from time to time for analysis, it will be found that the piperitols produced are initially richest in the cis-form, and that as the reaction proceeds they become richer in the transform until at last about equimolecular quantities of the cisand trans-forms are produced. Thus, if l-menthol is to be produced from d-limonene, the l-methoxy-Z-menthene derived therefrom is best processed with formic acid in the shortest time and with some sacrifice of l-methoxy-Z-menthene conversion, in order to secure a high ratio of cisto trans-piperitol, say 7 to 3. On the other hand, if l-limonene is employed and it is desirable to produce menthol via hydrogenation of trans-piperitol followed by equilibration of the isomenthol produced, it will be found desirable to secure higher conversions of l-methoxy-Z-menthene and permit desirable to secure maximum yields of cis-piperitol. Conversion of others to piperityl esters need not be complete as unchanged ether isreadily recovered. w p j A r. thatrsetmsnt .l .-.9 !P FId she rsastienimirty may or may not separate into two phases depending upon the'acid employed, whether solvents are present, upon concentration of the reactioningredients, etc. In employing the 85-90% formic acid of commerce, phases do ordinarily settle readily and good agitationis desirable during treatment. When treatment is complete, the lower aqueous formic acid is withdrawn and recycled or reconcentrated and the upper layer is saponified with an alkali or alkali earth in wateror alcohol. In general, aqueous caustic s' odalsolutionis satisfactory and cheapandwe lifefer to employ it. Saponification is conducted by he'at ing the mixture of aqueous alkali and the ester to'80 to 100 C. for a few hours.

Fractional distillation is conducted in vacuo at to 30 mm. absolute pressure at the condenser. I Distillation at higher pressures may tend to cause dehydrationof the unsaturatedalcohol. f I k I 1 Ordinarily we prefer to discontinue the esterification treatment before-the maximum amount of piperityl ester is formed,'particularly if the product under treatment is an other. In this way, maximum yields of piperitols are obtainable based on the amount of starting material con verted, since shorter treatments or less vigorous treatments result in less-loss of product through hydrocarbon formation, and unchanged material is readily recovered during the fractional distillation step.

I While it is preferred to employ acids for alcohol es terifications, it will be appreciated that other methods of esterification can 'be employed thoughless' e'conomically." It ispreferable to employ fairlyheoncentrated organic acids because through theirf use, good ally'l omerization conditions coexist withgood esterification conditions, and it is this simultaneous activity which permits most economic conversion of the tertiary alcohol allylomer to the piperityl derivative and the con- Version of one piperitol epimer to the other. Also, in the case of'etherconversions, splitting of the ether linkage and esterificationare best brought about in presence of acids. I

It has been found also. that ,a pipen'tyl ester fraction, rich in either the cisor transeform, can be treated under the preferred conditions with an jacid to form a piper-ityl ester containing more equal proportions of the two forms. Thus, as stated above, when l-methoxy-2- menthene is treated with formic acid for a short time,

the .piperityl formate produced is richest in" the cis-.

isomer. If the isolated piperitylformate rich in the cis-I isomer is again treated with formic acid, the piperityl formate recovered from the treatment will be less rich in the cis-form. t l 1 Perhaps the best explanationthat can be advanced to explain the related phenomenaYdescribedhs' that the tertiary alcohols and their ethers, the corresponding. sec: ondary alcohols and their ,ethers, and the esters of the secondary alcohols are all capable of and do generate a common ion when treated with acids under our preferred conditions, and that this ion reacts with the carboxylate ion of the acid to produce the mixed piperityl ester. Thus, it would be expectedthatif tr'ans piPerityI butyrate-were treated with a several molar excess of formic acid under our preferred conditions, there would 1 e qtsfi n t a e the samw ts Mar haame acid reagent. Thus, some ethers are more diflicult to hydrolyze and esterify than others. Thus, optimum con ditions in terms of conversion, reaction rates and the suppressionpf undesirable dehydration and polymerization may vary with each particular system undergoing treat; nient. M The following examples are illustrative ofthe vention: i

Example 1 Ten-ml. of B-2,8-menthadiene-1-ol was treated at room temperature, about 25 C., with 25 ml. formic acid. The homogeneous solution that resulted on mixing the reactants became dishomogeneous within a few minutes and a mildly exothermic reaction took place. After standing a few hours, the product was washed with Water and with aqueous alkali and dried. Its infrared spectrum showed it still contained some terminal methylenic 'unsaturation, no alcohol and appreciable formate ester. The sample was now saponified with alcoholic alkali and the unsaponifiable portion was isolated. The unsaponifiable matter was a rather viscous pale yellow oil whose infrared spectrum showed no carbonyl (ester) absorptions, and considerable isopiperitenol. It was evident, however, that the acid treatment was sufficiently vigorous to bring about the formation of some polymer.

Example 2 Ten ml. of [3-2,8-menthadiene-1-o1 and a solution of 5 g. sodium acetate in 25 ml. formic acid were cooled separately to 5 C., then mixed to form a homogeneous solution. After standing for 6 hours at about 10 C., the oil layer which had formed was separated and saponified with alcoholic caustic. The unsaponifiable fraction was isolated and was found by IR analysis to be almost pure isopiperitenol, though a mixture of cisand trans-forms was present. The much milder acid treatment in this case than the treatment of Example -1 produced. little or no polymer or dehydration of the alcohol.. I

' Example3 The experiment of Example 1 was repeated but at 5 C. with somewhat less polymerization, but some polymer was still present. I

I Y i Example4 Example-2 was repeated exactly, except that the alpha form of2-8-p-menthadiene-1-ol was employed. Almost pure' isopiperitenol resulted, butboth cisand transforms were present, as shown by the infrared analysis. This result shows that either the alpha or beta form of 2,8-p-menthadiene-l-ol can be employed to produce a mixture of the cisand trans-forms of isopiperitenol.

Example 5 Ten ml. ofi'sopiperitenyl methyl etherpobtained by fractionation of the pyrolysis products of verbenyl methyl ether, was cooled to 5 C. and treated with a cold mixture of 5 g. sodium acetate in 25 ml. formic acid. Thev reaction mixture was shaken at intervals, since some oilphase was present, and at the end of 8 hours an aliquot was saponified and the unsaponifiable WasanaIyZed by infrared methods. The product consisted of a mixture of unreacted ether and isopiperitenol, about 50-60% of the latter. Another aliquot of the reaction mixture was saponified and analyzed after a total of 20 hours reaction time. About 70% isopiperitenol was present, as was also some unchanged ether. In all cases, the isopiperitenol was a mixture of cis-trans forms.

Example 6 The experiment reported in Example 2 was repeated exactly, except that cis-2-p-menthene-1-ol and an 8-hour reaction time was employed for the treatment. In this case the alcohol did not become homogeneous with the buffered formic acid, and the mixture required occasional shaking. After 8 hours, the oil phase was separated, saponified, dried and submitted to infrared analysis, which showed the product to consist largely of a mixture of cis-and trans-piperitols.

Example 7 A buffered formic acid solution was prepared by dissolving 15 g. sodium acetate in =100 ml. 90% formic acid. Thirty ml. of this solution was mixed at about 25 C. with 10 g. of piperitol consisting of about 90% transand 10% cis-forms. Two phases were present, and the mixture was shaken at 30-minute intervals over a period of 4 hours. The piperityl formates were then separated and saponified with methanolic KOH. The infrared spectrum of the recovered piperitols showed that the product was about 45 trans-piperitol and about 50% cis-piperitol, thus showing that trans-piperitol was converted to cis-piperitol by the acid treatment.

Example 8 Buffered formic acid was produced by dissolving 15 g. sodium acetate in 100 ml. formic acid, 90%. Thirty ml. of buffered formic acid, 10 ml. of Z-p-menthene-l-ol and 25 ml. butyric acid were cooled separately to 8-10 C., tren mixed. The mixture was allowed to stand at 0-10 C. for 18 hours and remained homogeneous. This product was added to Water, and the resulting oil phase was washed with water and saponified. The resulting alcohols were analyzed by infrared methods and found to consist of a mixture of cisand trans-piperitols containing only small amounts of the cis and trans-Z-pmenthene-l-ols.

Example 9 Isopiperitenyl methyl ether, 882 g., was mixed with 8.8 g. of nickel catalyst in a rocking-type autoclave and hydrogenated at 340-605 p.s.i.g. at a temperature of about 110 to 124 C. Hydrogenation was stopped as soon as 0.979 mole of hydrogen per mole of ether had been absorbed. Infrared analysis showed that only 2 to of the exocyclic double bond remained, and that therefore the product was piperityl methyl ether. The product was distilled, and a portion, 582 g. (boiling largely at 7783 C. at 10 mm.), was treated with 582 g. of a buffered formic acid solution produced by treating 90% formic acid with 10% of its weight of sodium acetate. The reaction mixture was agitated at 2530 C. for 4 hours. The oil layer was then separated and saponified, dried and fractionated at 10 mm. pressure to obtain a piperitol fraction, B.P. 95-105 C.

About 40% of the saponified product was piperitol. the piperitols, about 55% was the trans-form.

Example 10 The pyrolysis of verbenyl ethers is disclosed in copending application Serial No. 397,464, filed December 10, 1953, now Patent No. 2,871,268. Pyrolysis of verbenyl ethers conducted according to the processes disclosed yields a pyrolyzate rich in isopiperitenyl ethers, pseudo-verbenyl ethers, enol ethers and lesser amounts of unreacted verbcnyl ether, hydrocarbons, polymeric an other materials.

Verbenyl methyl ether was heated at about 240 C. for 4 hours under autogenous pressure and in the liquid phase. A portion of the pyrolyzate was fractionated carefully to permit fairly accurate analysis of the individual fractions by infrared analysis. The analyses of the individual fractions permitted analysis of the crude pyrolyzate as follows:

Enol methyl ethers 12-15 Isopiperitenyl methyl ether 53.0 5-methoxy-1,8-p-menthadiene 5.0 Residue 8-10 Unidentified materials 3-5 To 3327 g. of the crude pyrolyzate there was added slowly and with stirring 75% of its weight of formic acid. The reaction was maintained at 20-27" C. Some cooling was necessary at first since the hydrolysis of the enol ethers to ketones is exothermic. After all the formic acid had been added, the mixture was agitated for four hours. At first the reaction mixture was homogeneous, but two phases were present after about one hour of reaction. After reacting for four hours, the organic layer was separated and washed with water and with 10% aqueous alkali to remove most of the formic acid and methyl formate, and then the oil layer was saponified with alcoholic alkali, then recovered and dried. The loss of weight to this point was 7.5%.

Fractional distillation at 10 mm. pressure resulted in recovery of a large number of fractions which were analyzed by infrared analysis. The lower boiling products consisting almost entirely of ethers, but with some hydrocarbons and amounting to about 45% of the starting crude pyrolyzate, were retreated with formic acid under substantially the same conditions, and the saponified products were fractionated an analyzed by infrared analysis.

The analyses of all the various fractions from the two treatments were collated to calculate the recovery of various products in terms of percent by weight of starting crude pyrolyzate as follows:

Percent Hydrocarbons 4.7 Pseudo-verbenyl methyl ether 9.9 5 -methoxy-1 ,8-p-menthadiene 5.1 Isopiperitenyl methyl ether 2.1 2,8-p-menthadiene-1-0l 1.4 Isopiperitenol 39.8 Ketones 8.1 Distillation residues 15.6 Unidentified 2.3

The isopiperitenol consisted of a mixture of cisand trans-forms and was not easily separated from the ketones which boil close to the alcohol.

It was subsequently discovered that the crude pyrolyzate might be treated with small amounts of acids to split the ketone enol methyl ethers selectively, and that the ketones so produced could be separated from the non-enolic ethers by distillation. The recovered ethers containing none or little of the enolic ethers could then be treated to form isopiperitenol which contained little or no ketone as impurity.

Example 11 Isopiperitenyl methyl ether, g., was added to a solution of 5 0 g. sodium acetate dissolved in 300 ml. 90% formic acid that had been cooled to about 0 C. The mixture, at about 89 C., was agitated and small samples were withdrawn periodically. These were saponified, and the saponification product was analyzed by infrared analysis for isopiperitenol.

Reaction time: Percent alcohol 20 minutes 6 1 hour 12 2 hours 17 6 hours 31 The entire reaction product was processed to obtain the sample for the 6-hour reaction time, and after saponification and drying, the product was distilled to recover fractions representing 55 of the original isopiperitenyl Example 12 The above reaction was repeated except that the temperature throughout the reaction was maintained at 26.5- 29.5 C. Samples were withdrawn periodically and saponified to recover the alcohol-rich product. The

product from the 'saponifica-tion of a sample of the formic acid treatment lasting 60 minutes contained 38% isopiperitenol and the product from saponification of a2- hour formic acid treatment contained 46% isopiperitenoi. About twice as much hydrocarbon was formed as in the preceding example.

Example 13 Isopiperitenyl methyl ether, 50 ml., and 100 ml. water were boiled for eig'ht-anda-half hours. oil layer was analyzed and found to contain 34% alcohols, largely the cisand trans-forms of 2.3-menthadicne-l-ol and smaller quantities of'isopiperitenol.

Example 14 Example 15 (A) Isopiperitenyl methyl ether, 10 ml., and 10 ml. of glacial acetic acid were mixed and allowed to stand for 24 hours. The ether was not split. I

(B) Isopiperitenyl methyl ether, 10 ml., was agitated with a mixture of 20. ml. acetic acid and ml. of 1% aqueous sulfuric acid and then allowed to stand for 24 hours at room temperature. After separating the oil layer and saponifyin it, the product was found to contain 46% alcohols, about half isopiperitenols and about half 2,8-pmenthadiene-l-ol. It was evident that while hydrolysis of the ether took place readily, the alcohols formed were only partly esterified.

(C) An aqueous solution of maleic acid was produced by boiling g'. maleic anhydride with cc. water, and this was cooled to 25 C.; then 10 ml. isopiperitenyl methyl ether was added. After agitating the mixture for 3 hours, it was saponified. The recovered oil contained a mixture of 22% alcoholsisomeric with isopiperitenol but poor in this component.

(D) ReactionC above was'repeated but in the presence of 3 ml. morpholine. At the end of 18.7 hours agitation, the product was separated and found to contain after saponification 32% alcohols isomeric with isopiperitenol but not rich in this component.

(E) Isopiperitenyl methyl ether, 10 ml., and 10 ml. of 90% aqueous acetic acid were mixed and allowed to stand for 19 hours. After saponification of an aliquot, little alcohol could be detected. In 46.2 hours, about 3% alcohol was present.

(F) A mixture of ml. dioxance, 5 ml. 90% formic acid and 10 ml.,isopiperitenyl methyl ether was allowed to stand 24 hours at room temperature and then saponified. Little or no alcohol was formed. 7

(G) lsopiperitenyl methyl ether, 20 ml., was agitated at room temperature for 24 hours with 100 ml. of 30% aqueous formic acid. About 50% of the ether was split and about 70% of the alcohols recovered after saponification was isopiperi'ten'ol. This reaction shows that even fairly dilute formic acid is effective in producing esters saponifiable: tov isopiperitenol, though more concentrated formic acid would have yielded isopiperitenol in higher proportion relative to the total alcohols present,

A sample of the ExamplesJd-SS 10-1111. samples of Lmethoxy-Z-menthehe were treated with various reagents at different temperatures for 'various lengths of time. At the end of the reactionsperiod, the acid reagent was washed out of the oily product first with water and then with sodium bicarbonate. The prod not, containing an ester of piperitol, was then saponified and analyzed by infrared analysis. The experiments show the need for adjustments in temperature, s'olvents' and time of reactions when various types of acids are employed in splitting l-methoxy-Z-menthene with acids to form piperityl esters.

m, w m. t}:

Ex. Reagent Tlme Temp. Result of treatment Hours C.

16 15 ml. 95% aqueous 120 ca. 20-25 About 5% piperitols,

butyrlc acid. remainder the starting other.

17 15 ml. 95% aqueous 160 ca. 20-25 About 7% piperitols,

propionic acid. remainder the starting ether.

18 10 m1. acetone plus 24 10 About 35% piperitols 15 ml. of 5% by and remainder weight oxalic acid largely starting in glacial acetic ether. acid.

19 do 120 10 Same as Example 18,

but trace of phellandrenes and slightly less uureacted ether.

20 15 ml. 95% glacial 22 2025 About 20% piperitols acetic acid but substantial containing 5% loss of ether due to oxalic acid. other reactions.

21 15 grams maleic acid, 22 2025 About 5% alcohols,

never dissolved most of starting completely in the ether had decomether. posed otherwise.

22 15 grams maleic acid 24 10 About piperl-' plus 15 ml. tols. considerable acetone unchanged others.

23 .do 120 10 A out 15% pipcritols and less unchanged other than in i Example 22. 24 15 mls. of a mixture 22 20-25 About 25% pipericonsistiug of 95% tols, remainder acetic acid, 2% largely ether and phosphoric acid phellandrenes. and 3% water.

25 .d0 24 10 37% piperitols,

V remainder largely ether.

26 do 120 10 37% piperitols, but considerably less other than in Example 25.

27 15 grams chloracetic 22 20-25 Most of the ether acid; mixture did was destroyed, but

not become only traces of homogeneous. alcohols were present.

28 10 ml. acetone and 24 10 About 25% piperi- 15 grams chlortols, but little acetic acid. starting ether 1 remained.

29 do 120 10 About 15% piperitols, but little starting ether remained.

30 15 ml. 95% aqueous 22 20-25 About piperiacetic acid. tols, remainder very largely unreacted ether.

31 do 144 20-25 About 42% piperitols, much less unreacted other glgan in Example 32...- 15 ml. glacial acetic 22 20-25 About 3% piperitols,

. acid. remainder unreacted starting e er.

33 15 ml. 95% aqueous 24 20-25 Trace of alcohol.

butyric acid containing 0.01%

34 15 ml. 95% aqueous 24 About 33% piperitol,

, butyrlc acid. remainder largely unchanged ether.

35 --do 24 About 31% piperitol,

. I but much less ether remaining than in Example 34.

Example 36 300 grams of trans-piperitol, a (10 cm.) 49', was added slowly to a mixture of 600 grams of formic acid and 90 grams of anhydrous sodium acetate at 0-5 Q.

Example 37 200 grams of l-cis-piperitol, ot (10 cm.) 255, is treated with 500 ml. glacial acetic acid at 10 C. The homogeneous solution is allowed to stand for 48 hours at 10 to 25 C., and then the excess acetic acid is removed by water wash. After neutralizing the oil layer by washing it with sodium bicarbonate solution, the ester is fractionated at mm. pressure. After removal of a small amount of free alcohols, 13.1. 70-85" C., containing some Z-menthene-l-ol, the pure piperityl acetate, B.P. 909'5 C. at 5 mm., distills. The ester shows N 1.462, D 0.950, 31 cm. tube). On saponification it yields a mixture of l-cis and d-trans-piperitols.

This application is a continuation-in-part of application Serial No. 382,839, filed September 28, 1953, and now Patent No. 2,894,040.

Having described the invention, what is claimed is:

l. The process for producing esters of A -3-hydroxy secondary alcohols of the p-menthane series which consists essentially in treating a mixture of a hydroxy compound of the p-menthane series selected from the class consisting of (1) those having a hydroxyl group at the t-position and a non-conjugated disubstituted double bond in the 2,3-position as the sole cyclic double bond and (2) those having a hydroxyl group in the 3-position and a a non-conjugated tri-substituted double bond in the 1,2- position as the sole cyclic double bond and a carboxylic acid at a hydrogen ion concentration in the range of that produced by boiling distilled water and 90% formic acid at a temperature of 0 C. to 100 C. for a time sufficient to bring about a substantial increase in the ester content of the mixture, whereby there is produced a mixture of the cis and trans forms of a carboxylic acid ester of a 3-hydroxy compound of the p-rncnthane series having a double bond in the 1,2-position.

2. The process of claim 1 in which the starting alcohol is a monohydric alcohol.

3. The process of claim 1 in which the hydroxy compound is produced in situ by hydrolysis from an ether thereof.

4. The process for producing esters of A -3-hydroxy alcohols of the p-menthane series which consists essentially in treating a mixture of a lower alkyl ether of a monohydroxy compound of the p-menthane series having the alkoxy group in the 1-position as the sole substituent on the molecule and a non-conjugated double bond in the 2,3-position as the sole cyclic double bond and a carboxyiic acid at a hydrogen ion concentration in the range of that produced by'boiling distilled water and 90% formic acid at a temperature of 0 C. to 100 C. for a time sufiicient to bring about a substantial increase in the ester content of the mixture whereby there is produced a mixture of the cis and trans forms of a carboxylic acid ester of a 3-hydroxy compound of the p-menthane series having the double bond in the 1-position.

5. The process for producing esters of A -3-hydroxysecondary alcohol of the p-menthane series which consists essentially in treating a mixture of a hydroxy compound acid at a temperature of 0 C. to [100 C. for a time sufficient to bring about a substantial increase in the ester content of the mixture, whereby there is produced a carboxylic acid ester of a B-hydroxy compound of the p-menthane series having a double bond in the 1,2- position.

6. The process of claim 5 in which the hydroxy compound is produced in situ by hydrolysis from an ether thereof.

7. The process of claim 6 in which the ether is a lower alkyl ether of l-hydroxy-Z-p-menthene.

8. The process of claim 6 in which the ether is a lower alltyl ether of l-hydroxy-2,8-p-rnenthadiene.

vpound is l-hydroxy-Z-p-menthene.

10. The process of claim 5 in which the hydroxy compound is 1-hydroxy-2,8-p-menthadiene.

ii. The process for producing esters of A B-hydroxysecondary alcohol of the p-menthane series which consists essentially in treating a mixture of a hydroxy compound of the p-menthane series having a hydroxyl group in the 3-position and a non-conjugated trisubstituted double bond in the 1,2-position as the sole cyclic double bond, which compound is predominately in one of the cis-trans forms thereof, and a carboxylic acid at a hydrogen ion concentration in the range of that produced by boiling distilled water and formic acid at a temperature of 0 C. to C. for a time suificient to bring about a substantial increase in the ester content of the mixture, whereby there is produced a carboxylic acid ester of the 3-hydroxy compound in which the amount of the form originally predominating is decreased and the amount of the form originally present in minor amount is increased.

12. The process of claim 11 in which the hydroxy compound is formed in situ by hydrolysis from an ether thereof.

13. The process of claim 12 in which the ether is a lower alkyl ether of 3-hydroxy-1,8-p-menthadiene.

14. The process of claim 12 in which the ether is a lower alkyl ether of piperitol.

15. The process of claim 11 in which the hydroxy compound is a 3-hydroxy-1,8-p-menthadiene.

16. The process of claim 11 in which the hydroxy compound is piperitol.

17. The process for producing esters of A -3-hydroxysecondary alcohol of the p-rnenthane series which consists essentially in treating a mixture of an optically active ly-hydroxy-Lp-menthene and a carboxylic acid at a hydrogen ion concentration in the range of that produced by boiling distilled water and 90% formic acid at a temperature of 0 C. to 100 C. for a time sufficient to bring about a substantial increase in the ester content of the mixture, whereby there is produced a mixture of optically active cisand trans-forms of piperityl ester, separating the cisand trans-forms of said ester and treating one of said separated forms with a lower aliphatic monocarboxylic acid to produce a mixture of optically active cisand trans-esters of piperitol.

l8. A process for producing a mixture of cisand trans-forms of optically active piperitol esters, which consists essentially in treating a mixture of carboxylic acid ester of one of said forms with a lower aliphatic monocarboxylic acid at a temperature between 0 C. and 100 C., whereby a mixture of optically active cisand transesters of piperitol and said monocarboxylic acid is formed.

OTHER REFERENCES Locquin et al.: Compt. Rend. 174 (1922), p. 1711-3. Simonsen et al.: The Terpenes," vol. 1 (1953), p. 286. 

1. THE PROCESS FOR PRODUCING ESTERS OF $1-3-HYDROXY SECONDARY ALCOHOLS OF THE P-METHANE SERIES WHICH CONSISTS ESSENTIALLY IN TREATING A MIXTURE OF A HYDROXY COMPOUND OF THE P-METHANE SERIES SELECTED FROM THE CLASS CONSISTING OF (1) THOSE HAVING A HYDROXYL GROUP AT THE 1-PISITION AND NON-CONJUGATED DISUBSTITUTED DOUBLE BOND IN THE 2,3-POSITION AS THE SOLE CYCLIC DOUBLE BOND AND (2) THOSE HAVING A HYDROXYL GROUP IN THE 3-POSITION AND A A NON-CONJUGATED TRI-SUBSTITUTED DOUBLE BOND IN THE 1,2POSITION AS THE SOLE CYCLIC DOUBLE BOND AND A CARBOXYLIC ACID AT A HYDROGEN ION CONCENTRATION IN THE RANGE OF THAT PRODUCED BY BOILING DISTILLED WATER AND 90% FORMIC ACID AT A TEMPERATURE OF 0*C. TO 100*C. FOR A TIME SUFFICIENT TO BRING ABOUT A SUBSTANTIAL INCREASE IN THE ESTER CONTINT OF THE MIXTURE, WHEREBY THERE IS PRODUCED A MIXTURE OF THE CIS AND TRANS FORMS OF A CARBOXYLIC ACID ESTER OF A 3-HYDROXY COMPOUND OF THE P-METHANE SERIES HAVING A DOUBLE BOND IN THE 1,2-POSITION. 